Sterile Area Ampoule Production Plant

Ahmed Sameh Gharieb, SLSS Process specialist Nov,2012

Objective
Clean Room Gowning Water Systems

Clean Rooms
What is a Clean room ?
it is defined in the International Organization for Standardization (ISO)

standard 14644-1 as: A room in which the concentration of airborne particles is controlled, and which is constructed and used in a manner to minimize the introduction, generation and retention of particles inside the room and in which other relevant parameters, e.g. temperature, humidity, and pressure, are controlled as as necessary. Clean room personnel clothing Gowning Later on Clean room Applications Types of Clean rooms

Clean Rooms

Clean room classification standards

The unit of measurement is a micrometer,

one micrometer (1 m) being one millionth of a meter. A human hair size approximately 70-100 m in diameter. PVC Thickness is 350 m

Cleanrooms are classified by the cleanliness of their air.

Pharmaceutical Clean Room Classification :- EU cGMP

Notes: (a) These are average values. (b) Individual settle plates may be exposed for less than 4 hours. (c) Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded operating procedures should prescribe corrective action.

5 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

 In cleanrooms of a high standard, where cleanliness

is a vital part of the production process, further testing or monitoring, may be required. Air pressure difference Clean room Airborne particle count Sampling Microbiological counts.
Air
Surfaces Volumetric Active sampling

Settle plates Passive

Personnel

Contact surfaces

Airborne Particle Counts

Volumetric Active sampling

A particle counter both counts and sizes particles in the air.

Different models : Some high-sensitivity models can count down to about 0.1 pm, but often with a

smaller air sampling volume

It uses a photodiode to sense light scattered by single particles passing through a

beam of light in a sensing zone. The light source is typically a laser diode.
The scattered light is concentrated by a lens system and converted by the photodiode

into electrical pulses, their amplitude being in proportion to the particle size. Thus, the size of particle can be measure

Volumetric Active sampling

Microbial Counts
Bacteria will normally be incubated for 48 hours at 30" C to 35" C; a further 72 hours at 20" C

to 25" C will allow fungi to grow. Colonies are counted, and hence the number of microorganisms that have been deposited can be ascerta
Petri dishes containing agar medium are opened (2*2)and exposed for a given period of

time, thus allowing microbe-carrying particles to deposit onto them. Petri dishes, 90 mm in diameter ined

Microbial Surface Sampling

Contact surface sampling RODAC (Replicate Organisms Detection And Counting dishes ) covered by a lid resting on a lip and gives
an agar meniscus that stands proud of the rim.

The agar is rolled over the clean room surface to be sampled.

Sampling plan frequency in Zone A , Zone B

Points to be considered

Gowning
Staff Training

Selection of clean room personal (Physiological ,

Psychological) Training on Specific GMP skills , Gowning , Microbiological sampling Gowning qualification . Frequency of changing garments Washing of garments separate laundry facility

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Gowning Zone A & B

Grade A and B
Headgear, beard and moustache covered, masks, gloves Not shedding fibres, and retain particles shed by operators

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Gowning Zone C, D and E

Clothing of appropriate quality:
Grade C Hair, beard, moustache covered single suit OVERALL (covering wrists, high neck), overshoes no fibres to be shed Sterile gloves , Mask Grade D Hair, beard, moustache covered , Mask and gloves protective clothing Green Overall and overshoes Grade E Hair ,Beard, covered and Overshoes
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Zone D

Zone E

Disinfectants and Sanitation

Preparation and Dilution Storage Labeling
Disinfectant Name Burton Divosan Savlon Dettol Isopropanol Conc. Used 2% 1% 0.5% 2% 70% Cleanliness zone A&B A&B C,D and E C,D and E A,B,C,D and E Usage Spraying Wiping and spraying Wiping and mobbing Wiping and mobbing Wiping

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Examples
1 Isopropyl Alchohol (70%)

Powerful disinfectant and antiseptic

Mode of action: Denatures proteins, dissolves lipids and can lead to cell membrane

disintegration Effectively kills bacteria and fungi

But does not inactivate spores!

2- Buraton 10 F
Liquid, aldehyde-based disinfectant concentrate Wide microbiocidal activity and are sporocidal and fungicidal. Mode of action: by denaturation of cell protein by reacting with

Cellular constituents.

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The Future !
Isolators :
Advantages
No direct contact between

operator & product ,..

Disadvantages :
??

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Why clean room MUST be cleaned ?

The main force that holds particles to cleanroom

surfaces is the London vander Waals force, this being an inter-molecular force. Electrostatic forces can also attract particles to a surface . Thus contamination will affect product Quality and Safety .

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Water for pharmaceutical Manufacturing processes

Introduction Different types of water
1-Potable 2-Process water Technical water 3-Purified water and Purified water Endotoxin free 4-Clean Steam and Water for Injection

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Water quality specifications

Potable water Apperance PH Clear 6.5-8.5 5-7 RO Water Clear Clear 5-7 WFI

Conductivity
TOC Total viable count

<,=1.3 (25)
<,=0.5 Alert limit
50cfu/ml

<,=1.3 (25)
<,=0.5 Alert limit
5cfu/100ml

Action limit
100cfu/ml

Action limit
10cfu/100ml

Bacterial endotoxin Absence of Ecoli forms

<0.25 EU/ml

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Principles

Like any starting material, production of water should conform to Good Manufacturing Practice (GMP) norms Potential for microbial growth Systems must be properly validated / qualified Water for parenteral use should not be contaminated with pyrogens or endotoxins Specifications and periodic testing are required

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Why purify raw water?

Although reasonably pure, it is always variable due

to seasonal variations, regional variation in water quality

Must remove impurities and control microbes to

avoid contaminating products

Treatment depends on waters chemistry and

contaminants, influenced by, e.g. erosion, pollution, dissolution, sedimentation, decomposition

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Contaminants of water (1)

There is no pure water in nature, as it can contain up to 90 possible unacceptable contaminants Contaminant groups: Inorganic compounds Organic compounds Solids Gases Microorganisms

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Microorganisms Biofilm formation Protozoa

Cryptosporidium Giardia Pseudomonas Gram negative, non-fermenting bacteria Escherichia coli and coliforms

Bacteria

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Background to water requirements and use

Water is the most widely used substance / raw

material
Used in production, processing, formulation,

cleaning, quality control

Unique chemical properties
Able to dissolve, absorb, adsorb, suspend

compounds and contaminants

Different grades of water quality available

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Types of water include:

Drinking water / potable water Purified water (PW) Highly Purified Water (HPW) Water for Injection (WFI)

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Water for Injections (WFI)

Prepared from potable water source

WFI is not sterile

WFI is not a final dosage form WFI is an intermediate bulk product According to The International and European Pharmacopoeias final purification step should be distillation

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Application of specific water to processes and dosage forms

Water used for different stages of:
Washing, preparation, synthesis, production,

formulation, control
Which grade of water is suitable for a particular

stage?
Consider nature and intended use of intermediate

or finished product, and stage at which water is used

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 Water treatment plants and distribution system

design, construction, maintenance operation and design capacity testing programme

Water for Injection (WFI)

produced, stored, distributed prevention of

growth of microorganisms constant circulation at temperature above 70, or not more than 4 degrees Celsius

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Manufacturing of Purified water

Principle of Reverse Osmosis

High pressure Low pressure

Semi-permeable membrane

Feed water under pressure

raw water

Purified water

Permeate water

drain or recycle
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Reject water

Comparison of different purification Ultra filtration VS Reverse osmosis methods

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 Water for Injection (WFI)

USP: . . .distillation or a purification process that is

equivalent of superior to distillation

Conductivity 1.3 S/cm @ 25 C Total Organic Carbon (TOC) 500 ppb Microbial 10 cfu / 100 ml Endotoxin requirement < 0.25 EU/ml

EP: . . .distillation JP: . . .distillation. . .or by the Reverse Osmosis

Ultrafiltration of Purified Water

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WFI System Main issues arise

Main issues arise Capacity and output capability Space needed for installation and structural loading

of premises Access needed for maintenance Sampling points

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Environmental Monitoring II
Physical
Particulate matter
Differential pressures Air changes, airflow patterns Clean up time/recovery Filter integrity

Temperature and relative humidity

Airflow velocity
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 Frequent, thorough cleaning of areas necessary Written programme Regular monitoring to detect resistant strains of

microorganisms
Chemical disinfection Monitoring of disinfectants and detergents Dilutions
clean containers, stored for defined periods of time Sterilized before use, when used in Grade A or B

areas
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Sterile Production
Manufacture of sterile preparations
To reach Grade B, C and D, the number of air changes

should be appropriate to the size of the area, number of personnel, equipment present
Minimum of 20 air changes per hour

Clean-up time about 15 20 minutes

Good airflow pattern in the area HEPA filtered air Suitable methods to determine particulate matter and

micro e.g. EU, ISO, Japan, USA

Thank you !